GSK3β inhibition protects the immature brain from hypoxic-ischaemic insult via reduced STAT3 signalling

• Hypoxic-ischaemic (HI) injury is an important cause of neurological morbidity in neonates. HI leads to pathophysiological responses, including inflammation and oxidative stress that culminate in cell death. Activation of glycogen synthase kinase 3β (GSK3β) and the signal transducer and activator of transcription (STAT3) promotes brain inflammation. The purpose of this study was to test whether inhibition of GSK3β signalling protects against neonatal HI brain injury. Mice were subjected to HI at postnatal day (PND) 9 and treated with a selective GSK3β inhibitor, SB216763. Brain injury and caspase-3 activation, anti-oxidant and inflammatory mRNA responses and activation of STAT3 were analysed. Our results show that HI reduced phosphorylation of GSK3β, thus promoting its kinase activity. The GSK3β inhibitor reduced caspase-3 activation and neuronal cell death elicited by HI and reverted the effects of HI on gene expression of the anti-oxidant enzyme sod2 and mitochondrial factor pgc1α. The HI insult activated STAT3 in glial cells and GSK3β inhibition attenuated STAT3 phosphorylation and its nuclear translocation following HI. Further, GSK3β inhibition reduced HI-induced gene expression of pro-inflammatory cytokines tnfα and Il-6, while promoted the anti-inflammatory factor Il-10. In summary, data show that GSK3β inhibition is neuroprotective in neonatal HI brain injury likely via reduced pro-inflammatory responses by blocking STAT3 signalling. Our study suggests that pharmacological interventions built upon GSK3β silencing strategies could represent a novel therapy in neonatal brain injury. © 2015 Elsevier Ltd. All rights reserved.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

Nyckelord

GSK3β

Hypoxia-ischaemia

Neuroinflammation

Oxidative stress

Perinatal

STAT3

2 (2

4 dichlorophenyl) 3 (1 methyl 3 indolyl)maleimide

caspase 3

glycogen synthase kinase 3beta

interleukin 10

interleukin 6

STAT3 protein

tumor necrosis factor alpha

animal cell

animal experiment

animal model

animal tissue

antioxidant activity

apoptosis

Article

brain blood flow

brain hypoxia

brain infarction size

cell death

cell fractionation

cell loss

cell proliferation

cell survival

controlled study

cytokine release

encephalitis

enzyme activation

enzyme inhibition

gene

gene expression

gene translocation

glia cell

Il 10 gene

Il 6 gene

mouse

nerve cell

neuroprotection

newborn

nonhuman

pgc1alpha gene

priority journal

protein phosphorylation

signal transduction

sod2 gene

tnfalpha gene

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)